Current Status of Patient-Controlled Analgesia in Cancer Patients

Current Status of Patient-Controlled Analgesia in Cancer Patients

In patients with an advanced disease or a terminal illness, it may become
necessary to institute parenteral opioid therapy either on a temporary
basis (for acute breakthrough pain) or permanently. Continuous intravenous
or subcutaneous opioid infusions have been the mainstay of parenteral opioid
therapy for oncologic pain. Patient-controlled analgesia (PCA) now offers
an alternative modality, and Drs. Bruera and Ripamonti review the current
status of this relatively new technique. Is there any evidence to suggest
the superiority of one modality over the other for the treatment of oncologic
pain?

Comparison of Efficacy of PCA and Continuous-Infusion Modalities

Bruera and co-workers reported on a crossover study that compared 3
days of continuous subcutaneous hydromorphone infusion vs patient-controlled
subcutaneous hydromorphone for the treatment of cancer pain.[1] The demand
dose selected for PCA was equivalent to the cumulative hydromorphone dose
administered over 4 hours of infusion. Supplemental doses were allowed
for breakthrough pain during both phases of the crossover study.

A total of 22 patients were evaluated for daily dose of hydromorphone,
number of supplemental doses for breakthrough pain, pain intensity, sleepiness,
anxiety, depression, and nausea during the two study phases. In addition,
patient preference for either mode of therapy was elicited at the study's
end. There were no statistical differences between the two groups with
regard to any of the aforementioned end points.

The major question that a crossover design can address is patient preference
for one mode of therapy. It is interesting to note that 7 patients preferred
PCA, while 10 patients preferred continuous-infusion therapy. Because of
the small sample size, no real determination of preference can be made
from the data.

To determine whether a particular technique is superior to another requires
a prospective study with large numbers of patients so that true differences
between treatments can be seen. Such a multicenter endeavor has recently
been completed by the Cancer and Leukemia Group B (CALGB).[2] This study
randomized 79 inpatients with severe cancer pain to either PCA or continuous
intravenous morphine for 5 days. The PCA group took significantly less
morphine than the continuous-infusion group over the 5 days. While mean
pain intensity for days 2 through 5 was significantly higher in the PCA-treated
patients, mean pain relief was similar in the two groups. Patients on PCA
had less psychological distress than patients on the morphine infusion;
moreover, patients on PCA who experienced the least sedation had the lowest
distress of all.

The results of this study will not be fully available until the manuscript
is published. Nonetheless, it appears that patients on PCA minimized sedation
and reduced psychological distress by administering less morphine. Perhaps
patients' perception that they can, at any time, control pain relief allows
them to tolerate greater pain intensity in order to lessen psychological
distress.

These results support the superiority of intravenous PCA over continuous
intravenous morphine for hospitalized patients with severe cancer pain.

PCA as a Clinical Regimen for the Treatment of Cancer Pain

The studies to date indicate that pure PCA can be safely and effectively
administered subcutaneously or intravenously, either in the inpatient or
outpatient setting. For the purposes of optimizing therapy, treatment should
be started in the hospital, as was done in the CALGB study,[2] so that
accurate assessments of response and toxicity can be made.

If the analgesic requirements of the patient are unknown, single injections
of intravenous morphine (2 to 5 mg) can be given every 15 to 20 minutes
until pain relief is achieved. This "loading" should be performed
over 4 hours to allow sufficient time to evaluate the patient's analgesic
needs. At the end of 4 hours, the cumulative amount of morphine is divided
by the time spent in the loading period in order to calculate the hourly
morphine dose. For example, if 20 mg of morphine were given over 4 hours,
the hourly morphine requirement would be 5 mg/h.

Over the next 4 hours, the patient is permitted to self-administer 60%
of the hourly dose (3 mg) as the demand dose, with a lock-out interval
of 10 minutes. This accomplishes final "titration" of the patient's
analgesic requirement. A demand dose is then selected that equals the amount
of opioid used over a preceding 90- to 120-minute period. This is given
with a 15-minute lock-out interval. For example, if the patient self-administered
eight (3-mg) doses over 240 minutes, a demand dose of 9 to 12 mg is given,
with a lock-out interval of 15 minutes.

For patients with known narcotic exposure, the amount of morphine per
hour can be calculated using a 3:1 ratio in converting oral to intravenous
or subcutaneous drug. A demand dose is then selected that equals the amount
of opioid used over a 60- to 120-minute period, with a lock-out interval
of 15 minutes. The patient should be monitored for toxicity and reevaluated
approximately 4 and 8 hours later to evaluate adequacy of pain relief.

Patients with cancer will tolerate large demand doses, as the intensity
of their pain is great. They are not "opioid-naive" and have
developed some degree of tolerance to opioids. The dosing regimen just
outlined is designed for patients with oncologic pain and cannot necessarily
be extrapolated for use with other types of patients or pain models, such
as postoperative pain. Likewise, a 1-mg dose with a 6-minute lock-out interval,
as has been used for postoperative pain, is not practical for a cancer
patient with chronic pain who may require long-term use of PCA. Higher
doses of morphine prevent cancer patients from self-administering medication
so frequently that it would interfere with their activity.

A continuous opioid infusion plus patient-controlled demand mode is
another therapeutic option. However, the proper ratio of the continuous
infusion to the demand mode needs to be better defined and individualized
to the patients' unique pain pattern. One approach for the patient with
chronic cancer pain is to give 50% of the total daily narcotic dose as
a continuous infusion supplemented initially by a demand dose that is 50%
to 100% of the hourly rate, with a lock-out interval of 30 to 60 minutes.

Over time, some individuals develop analgesic tolerance to this type
of regimen, requiring frequent dose escalation. As noted above, if less
narcotic reduces psychological distress, one might rely on pure PCA during
the daytime and a combination of PCA and continuous infusion during the
night hours. Thus, these two modes of delivering PCA are not mutually exclusive.

Patient-controlled analgesia can be adequately monitored by following
patients' respiratory rate and mental status. In individuals with a normal
baseline respiratory rate, a decrease of 40% or more, attended by clinical
manifestation of hypoxemia or somnolence, indicates the need for closer
observation and adjustment of dosing parameters.

Summary

In summary, recent trials have demonstrated that PCA is a safe and effective
means for relieving cancer- associated pain. Conducting prospective trials
on PCA is labor-intensive because of the data management necessary to evaluate
its many end points. However, these trials will better define its unique
merits and optimal use in oncology patients.